Glatiramer Acetate modulates ion channels expression and calcium homeostasis in B cell of patients with relapsing-remitting multiple sclerosis.

To investigate the effects of Glatiramer Acetate (GA) on B cells by an integrated computational and experimental approach. GA is an immunomodulatory drug approved for the treatment of multiple sclerosis (MS). GA effect on B cells is yet to be fully elucidated. We compared transcriptional profiles of B cells from treatment-naïve relapsing remitting MS patients, treated or not with GA for 6 hours in vitro, and of B cells before and after six months of GA administration in vivo. Microarrays were analyzed with two different computational approaches, one for functional analysis of pathways (Gene Set Enrichment Analysis) and one for the identification of new drug targets (Mode-of-action by Network Analysis). GA modulates the expression of genes involved in immune response and apoptosis. A differential expression of genes encoding ion channels, mostly regulating Ca2+ homeostasis in endoplasmic reticulum (ER) was also observed. Microfluorimetric analysis confirmed this finding, showing a specific GA effect on ER Ca2+ concentration. Our findings unveils a GA regulatory effect on the immune response by influencing B cell phenotype and function. In particular, our results highlight a new functional role for GA in modulating Ca2+ homeostasis in these cells.

Growth hormone/IGF-1 axis longitudinal evaluation in clinically isolated syndrome patients on interferon ß-1b therapy: stimulation tests and correlations with clinical and radiological conversion to multiple sclerosis.

BACKGROUND AND PURPOSE: Growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis abnormalities in multiple sclerosis (MS) suggest their role in its pathogenesis. Interferon ß (IFN-ß) efficacy could be mediated also by an increase of IGF-1 levels. A 2-year longitudinal study was performed to estimate the prevalence of GH and/or IGF-1 deficiency in clinically isolated syndrome (CIS) patients and their correlation with conversion to MS in IFN treated patients. METHODS: Clinical and demographic features of CIS patients were collected before the start of IFN-ß-1b. IGF-1 levels and GH response after arginine and GH releasing hormone + arginine stimulation tests were assessed. Clinical and magnetic resonance imaging evaluations were performed at baseline, 1 year and 2 years. RESULTS: Thirty CIS patients (24 female) were enrolled. At baseline, four patients (13%) showed a hypothalamic GH deficiency (GHD), whilst no one had a pituitary GHD. Baseline demographic, clinical and radiological data were not related to GHD, whilst IGF-1 levels were inversely related to age (P < 0.001) and GH levels (P = 0.03). GH and IGF-1 serum mean levels were not significantly modified after 1 and 2 years of treatment in the whole group, although 3/4 GHD patients experienced a normalization of GH levels, whilst one dropped out. After 2 years of treatment 13/28 (46%) patients converted to MS. The presence of GHD and GH and IGF-1 levels were not predictive of relapses, new T2 lesions or conversion occurrence. CONCLUSIONS: Growth hormone/IGF-1 axis function was found to be frequently altered in CIS patients, but this was not related to MS conversion. Patients experienced an improvement of GHD during IFN therapy. Longer follow-up is necessary to assess its impact on disease progression.

Powerhouse failure and oxidative damage in autosomal recessive spastic ataxia of Charlevoix-Saguenay.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease due to mutations in SACS, which encodes sacsin, a protein localized on the mitochondrial surface and possibly involved in mitochondrial dynamics. In view of the possible mitochondrial involvement of sacsin, we investigated mitochondrial activity at functional and molecular level in skin fibroblasts obtained from ARSACS patients. We observed remarkable bioenergetic damage in ARSACS cells, as indicated by reduced basal, adenosine triphosphate (ATP)-linked and maximal mitochondrial respiration rate, and by reduced respiratory chain activities and mitochondrial ATP synthesis. These phenomena were associated with increased reactive oxygen species production and oxidative nuclear DNA damage. Our results suggest that loss of sacsin is associated with oxidative stress and mitochondrial dysfunction, and thus highlight a novel mechanism in the pathogenesis of ARSACS. The involvement of mitochondria and oxidative stress in disease pathogenesis has been described in a number of other neurodegenerative diseases. Therefore, on the basis of our findings, which suggest a potential therapeutic role for antioxidant agents, ARSACS seems to fall within a larger group of disorders.

[Implantation of a program of terminal evaluation of graduating medicalstudent performance to estimate the efficacy of the curriculum in the ++Ribeirão Preto Medical School]. / Implantação de um programa de avaliação terminal do desempenho dos graduandos para estimar a eficácia do currículo na Faculdade de Medicina de Ribeirão Preto.

PURPOSE: To describe the main steps in the implementation of such assessment, as well as to present the measures taken in order to overcome the difficulties that have been found. METHODS: The proposed two-step assessment consists of a test of cognitive aspects based on Multiple Choice Questions (MCQ) and practical exams of clinical skills in each of 5 terminal areas. Students enrolled as volunteer for either step or both. The examinations were developed and carried out by faculty members nominated by the involved Departments under the supervision of an institutional work group. The rates of student enrollment for the summative assessment has been recorded and the responses of both students and faculty members were evaluated by means of specific questionnaires. RESULTS: In the first two years, adhesion of students to the MCQ test was consistently high, but volunteering to the practical exams was persistently low. Moreover, there was a sharp decrease in faculty involvement, from the first to the second year. To overcome these difficulties, a number of measures were implemented aiming at increasing student adhesion and faculty involvement, as well as to improve assessment methods. As a consequence, a remarkable increase in both student adhesion and faculty involvement was recorded. CONCLUSION: The measures taken resulted in sharp increases in both acceptance of the proposed assessment and the quality of the examination methods, which have allowed a more reliable characterization of the strenghts and weaknesses of the local curriculum.

Implantaçäo de um programa de avaliaçäo terminal do desempenho dos graduados para estimar a eficácia do currículo na Faculdade de Medicina de Ribeiräo Preto / Implantation of program of terminal evaluation of graduating medical students performance to estimate the efficacy of the curriculum in the Faculdade de Medicina de Ribeiräo Preto

Nos últimos cinco anos, um programa de avaliação final do desempenho dos graduandos vem sendo desenvolvido na Faculdade de Medicina de Ribeirão Preto, visando colher dados sobre a eficácia do currículo médico. Objetivo. Descrever as principais etapas de implantação deste programa, bem como as medidas tomadas para superar as dificuldades encontradas. Métodos. A avaliação consiste em uma prova de conhecimento e em exames práticos de habilidades. As provas são elaboradas e aplicadas por docentes das áreas envolvidas sob a supervisão de um grupo coordenador supra-departamental, que avalia todo o programa. Os graduandos participam como voluntários e os resultados são utilizados somente para os fins institucionais propostos. A adesão dos graduandos foi registrada e as impressões dos docentes e dos graduandos sobre o programa foram colhidas por meio de questionários específicos. Resultados. Nos dois primeiros anos a adesão dos graduandos à prova de conhecimento foi superior a 85 por cento, mas o percentual de inscrições nas provas práticas foi de apenas 55 por cento. Além disso, do primeiro para o segundo ano, houve diminuição considerável do grau de empenho dos docentes envolvidos, obrigando medidas corretivas voltadas ao recrutamento dos graduandos, à participação docente e aos métodos de avaliação prática. Em conseqüência, houve aumento notável da adesão dos estudantes que atingiu mais de 90 por cento nos anos seguintes. Houve, também acréscimo considerável do empenho docente, o que garantiu adequado nível de qualidade à avaliação. Conclusão. As medidas tomadas aumentaram a aceitação do programa e a qualidade das provas, permitindo que a avaliação do desempenho dos graduandos traga dados fidedignos sobre a eficácia do currículo.

Influence of gender on specialty choices in a Brazilian medical school.

PURPOSE: To examine the influence of gender on the specialty choices of graduates from a Brazilian medical school. METHOD: Data for graduates of the Faculty of Medicine of Ribeirao Preto, University of São Paulo (FMRP-USP) who enrolled in the FMRP-USP's residency program were pooled for surgery, internal medicine, pediatrics, obstetrics-gynecology, anesthesiology, ophthalmology, radiology, and orthopedics and were analyzed by gender in two periods, 1979-1984 (n = 414) and 1989-1994 (n = 407). The data were analyzed statistically by the chi-square test and Fisher's exact probability test. RESULTS: Women predominated in pediatrics and men in surgery and orthopedics in both periods, with no predominance of either gender in the other specialties. Between the two study periods, there were decreases in the choices of both genders for internal medicine and increases in the choices of the men for anesthesiology and of the women for radiology. CONCLUSION: Significant changes occurred in the pattern of specialty choices between the men and the women and the two study periods. Considering the needs of the Brazilian health care system, the trends in career choices and the influence of gender should be continuously scrutinized.